Prevention of Colorectal Cancer: An Emerging Role for High-Dose Vitamin D Supplementation?

Colorectal cancer is the second most common cause of cancer death in the United States. It is estimated that about 55,000 patients will die this year due to advanced colorectal cancer. These grim statistics persist despite a marked increase in the rate of screening colonoscopies and improvements in adjuvant chemotherapy. Successful chemoprevention strategies may reduce the risk of new colorectal cancers, thus decreasing related overall morbidity and mortality.

Attempts at Chemoprevention

Unfortunately, the investigation of several chemoprevention agents in polyp prevention, an imperfect surrogate of colorectal cancer risk, did not result in any major breakthroughs. A controlled randomized wheat bran supplementation trial failed to show any significant decrease in the rate of adenomatous polyp recurrence in patients with previously resected adenomas.[1] Another controlled randomized study of calcium carbonate, 3,000 mg/d, showed a moderate decrease in risk of polyp recurrence that barely reached statistical significance.[2]

Daily aspirin supplementation was also investigated in the prevention of polyp recurrence in two large controlled studies.[3,4] One randomized study showed a significant reduction in polyp recurrence among patients with resected colon cancer receiving 325 mg of aspirin per day.[4] However, the second study showed a significant reduction in polyp recurrence in a population of patients with a history of resected polyps only in the arm receiving low-dose aspirin at 81 mg/d.[3] Given the risks of bleeding associated with aspirin use, it would be unjustified to implement widespread use of low-dose aspirin for the purpose of colorectal cancer prevention.

Celecoxib (Celebrex), a selective cyclooxygenase (COX)-2 nonsteroidal inhibitor associated with a decreased risk of gastrointestinal bleeding, has been shown to reduce the risk of polyp recurrence.[5,6] However, this agent is unlikely to be used any further in large-scale prevention efforts, given its association with an increased incidence of cardiovascular events.[6]

Recently, the Women's Health Initiative (WHI) study reported on the value of vitamin D at 400 IU/d in combination with 1,000 mg/d of elemental calcium vs a matched placebo in more that 36,000 postmenopausal women.[7] Participants in this study received vitamin D or placebo for an average of 7 years. No reduction in the risk of colorectal cancer was noted on the treatment arm.[7] This is the only adequately powered prevention study so far to use colorectal cancer incidence as an outcome measure for colorectal cancer prevention. Despite the negative results from the WHI study, a growing body of preclinical and clinical evidence supports the use of vitamin D3 supplementation for the purpose of colorectal cancer prevention.

Underlying Pathophysiology

Normal, precancerous, and cancerous colonic epithelium may be targets of vitamin D through its direct effect on vitamin D receptors (VDR).[8-12] VDR expression increases in the progression from normal mucosa to premalignant or early malignant tissue (aberrant crypt foci, polyps, and differentiated adenocarcinoma).[10,12] VDR is the target of the active vitamin D compound 1,25 hydroxy-vitamin D (1,25-OH D3), and the binding of this compound to VDR results in antiproliferating and differentiating activities. The importance of VDR activation in preventing carcinogenesis has been demonstrated in several preclinical models. An inverse relationship between cellular proliferation and VDR expression was demonstrated in mouse colon.[13] Furthermore, complete loss of VDR (knockout mice) was associated with an increased proliferation and increased oxidative DNA stress, which may promote carcinogenesis.[13,14] In addition, vitamin D3 antitumor activity was documented in an APCmin mouse model.[15]

Vitamin D3 antiproliferative effects on colonic epithelium have also been demonstrated in human subjects. The supplementation of vitamin D3 in combination with calcium carbonate was shown to reduce the proliferative index and increase VDR expression in colonic polyps and mucosa.[16] Furthermore, an inverse relationship between serum 25-OH D3 levels and whole-crypt proliferative index had been previously documented.[17]